Calcium channel blockers were identified as a method for the control of hypertension, as reported by Fleckenstein et al., Z. Kreislaufforsch, 56, 716 (1967), and are routinely used in the control of hypertension. Three calcium channel blockers are currently of clinical significance in the United States, verapamil, nifedipine and diltiazem. All three achieve their anti-hypertensive effect by inhibiting the entry of calcium ions into vascular smooth muscle. The ultimate effect is vasodilation.
Hypertensive hormones, such as the renin-angiotensin system (RAS), the vitamin D system, and the parathyroid hypertensive factor (PHF), are all causative factors in stimulating the increase of calcium ions in vascular smooth muscle. PHF is disclosed and described in patent application Ser. No. 07/327,450.
It has been found that calcium supplements, in dietary form, may inhibit the RAS, PHF and vitamin D systems, Park et al., Am. J. Physiol., 235, F22 (1978); Park et al., Am. J. Physiol.,240, F70 (1981); Hotchen et al., Am. J. Cardiol., 62, 41G (1988); Bukoski et al., B.B.R.C., 147, 1330 (1987); Inoue et al., B.B.R.C., 152, 1388 (1988); Baran et al., J. Clin. Invest., 77, 1622 (1986); Lewanczuk et al., Am. J. Hypertens., 3:349 (1990)! and are, therefore, beneficial in decreasing calcium uptake in vascular smooth muscle. An untoward effect of calcium supplementation is that the increased bio-availability of calcium partially negates the inhibitory effect on the endocrine system. Calcium channel blockers, by limiting the uptake of calcium in vascular smooth muscle, are beneficial, but have been found to stimulate some endocrine systems, such as the RAS system. (Kotchen et al., Am. J. Cardiol., 62 41G (1988); Matsumara et al., J. Pharmacol. Exp. Ther., 241, 1000 (1978); Resnick et al., Fed. Proc., 45, 2739 (1986)). Utilization of calcium channel blockers may be limited by excessive vasodilation, negative inotropy, excessive depression of the sinus nodal rate, atrial-ventricular nodal conduction disturbances and interference with non-vascular smooth muscle contraction. A combination therapy which minimizes the amount of calcium channel blocker required to achieve the desired anti-hypertensive effect is desirable.
In addition to identification of essential hypertension, the existence of PHF is applicable to the study and treatment of other diseases which may or may not necessarily include hypertension as a primary symptom. These diseases include non-insulin-dependent diabetes mellitus (NIDDM) and cancer. In NIDDM, increased intracellular free calcium has been observed. The increase can be attributed to PHF. PHF has been detected in the plasma of "ob/ob" mice which are obese, hypertensive and have non-insulin-dependent diabetes. PHF is also found in humans with essential hypertension, e.g., hypertension of the low-renin and salt-sensitive type, and in a higher percentage of humans with NIDDM than those without NIDDM see Ho et al., Journal of Cardiovasc. Pharmacol., 23 (Supp. 2): S31-S34 (1994)!.
Some forms of cancer are characterized by an increase in intracellular free calcium see: Okazaki et al., Canc. Res., 46 (12 Pt 1), 6059-6063 (1986); Lipton and Morris, Canc. Chemother. Pharmacol., 18(1), 17-20 (1986); Chien and Warren, Canc. Res., 46(11), 5706-5714; Shirakawa et al., Canc. Res., 46(2), 658-661 (1986); and Meyer, J. Hypertens., 5 (suppl. 4), S3-S4 (1987)!. As PHF is of parathyroid origin, PHF may be implicated in those forms of cancer characterized by an increase in intracellular calcium concentration.